Participation of mucosal type I interferon signaling in pulmonary host defenses mucosal epithelial cells provide both barrier and signaling functions to initiate innate immune responses to bacterial infection in the respiratory tract. Particularly in the airways, the regulation of this initial proinflammatory signaling is critical. In addition to activating NF-?B-dependent proinflammatory genes in response to pathogens, airway mucosal cells also produce type I interferons, IFNs a and [unreadable] which result in Jak-Stat signaling and the activation of >300 effectors of the IFN-[unreadable] cascade. This cascade is best known for its major role in protection from viral infection, but is likely to have important effects on host defense against bacterial infection as well. In this project we will characterize how common mucosal pathogens, S. pneumoniae, S. aureus and P. aeruginosa activate type I IFN signaling;by identifying the receptors and signaling components that are activated in mucosal epithelial cells and by characterizing how these effectors affect susceptibility to infection. IFN-[unreadable] expression is significantly increased in the airways in response to influenza infection. The local consequences of upregulated IFN-[unreadable] signaling are postulated to enhance susceptibility to secondary bacterial infection, the major cause of influenza- associated mortality. This will be tested in a murine model of influenza, using influenza mutants with differing abilities to stimulate IFN-[unreadable] production and comparing how they affect susceptibility to bacterial superinfection. We predict that mucosal epithelial IFN-[unreadable] production, possibly through effects in activating pulmonary dendritic cells, increases host susceptibility to infection by common bacterial pathogens. Participation of mucosal type I interferon signaling in pulmonary host defenses RELEVANCE: This project will establish the how common mucosal pathogens, S. pneumoniae, S. aureus and P. aeruginosa activate type I interferon signaling in the respiratory tract. These interferons are critical for effective anti-viral defenses but appear to increase susceptibility to bacterial infection. Activation of this cascade may be an important factor contributing to post-influenza bacterial pneumonia, the major cause of mortality associated with influenza infection.